Patent GB-800738-A (GB)
Title: Water-insoluble salts of streptomycin antibiotics and pharmaceutical preparations containing same
Inventor: WOLF MILTON
IPC: C07G11/00
Filed: 1956-02-28
Abstract: The invention relates to non-toxic waterinsoluble salts of streptomycin, hydroxystreptomycin, dihydrostreptomycin or streptomycylidene isonicotinylhydrazine with a polycarboxylic acid having one of the formul  <FORM:0800738/IV (b)/1> wherein R1 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl; R2 is hydrogen, carboxyl or carboxymethyl; R3 is hydrogen, carboxyl, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl; R4 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl; R5 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl.  They are produced by neutralizing the acid with aqueous alkali metal, e.g. sodium hydroxide, and adding an aqueous solution of a water-soluble salt of the streptomycin antibiotic. The invention includes salts of one of the above acids with two different streptomycin antibiotics, e.g. streptomycin and dihydrostreptomycin. The acids may be in the form of a mixture of the optical and stereo isomers.  Examples relate to the preparation of (a) streptomycin levopimeric - 6,8a - cis - endosuccinate; (b) dihydrostreptomycin levo-pimaric-6,8a-cis-endosuccinace; (c) hydroxystreptomycin levo-pimaric-6,8a - cis - endosuccinate; (d) dihydrostreptomycin levo - primaric - 6,8a - trans - endosuccinate; (e) hydroxystreptomycin levo-primaric-6,8a trans - endosuccinate; (f) streptomycin levo - pimaric - 6,8a - trans - endosuccinate; (g) streptomycylidene isonicotinyl hydrazine levo - pimaric - 6,8a - cis - endosuccinate; (h) streptomycylidene isonicotinyl hydrazine levo-pimaric-6,8a-trans-endosuccinate, and others.  The salts may be used therapeutically (see Group VI) and in the purification of the antibiotics, especially streptomycin and dihydrostreptomycin from aqueous solution.  The polycarboxylic acids or their anhydrides are prepared from levo-pimaric acid according to the following equations and are separated by recrystallization into their isomers when such occur.  The reactions are conducted according to the procedure of Diels and Alder at less than 75 DEG  C.  In the equations R= represents the radical <FORM:0800738/IV (b)/2> with two free valencies as indicated and L.P.A. represents levo-pimaric acid. <FORM:0800738/IV (b)/3> United States Patent 2,517,563 is referred to.  Reference has been directed by the Comptroller to Specification 724,863.ALSO:Pharmaceutical preparations comprise a water-insoluble salt of streptomycin, hydroxystreptomycin, dihydrostreptomycin or streptomycylidene isonicotinyl hydrazine with a polycarboxylic acid having one of the formul  <FORM:0800738/VI/1> <FORM:0800738/VI/2> <FORM:0800738/VI/3> <FORM:0800738/VI/4> <FORM:0800738/VI/5> <FORM:0800738/VI/6> wherein R1 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl; R2 is hydrogen, carboxyl or carboxy methyl; R3 is hydrogen, carboxyl, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl; R4 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl, R5 is hydrogen, halogen, alkyl, monocyclic carbocyclic aryl or cyclohexyl (see Group IV (b)).  The acids may be in the form of a mixture of the optical and stereo isomers.  Salts of one of the above acids with two different streptomycins, e.g. streptomycin and dihydrostreptomycin are included.  The preparations may be a suspension in (a) an iniectable oil, e.g. peanut oil; (b) a gelled injectable oil, e.g. peanut and aluminium monostearate; and (c) an aqueous diluent which may contain a suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gum tragacanth, gelatine, pectin and alginates.  The salts may be coated with, e.g., lecithin.  The salts may be used in conjunction with one or more of the following drugs: (a) antihistamines; (b) sulpha drugs; (c) vitamins; (d) lipotropic agents; (e) stimulants of the central nervous system; (f) analgesics; (g) laxatives; (h) sedatives; (i) antibiotics, e.g. bacitracin, neomycin, polymyxin, tyrothricin, erythromycin, tetracycline, chlortetracycline, oxytetracycline, "Magnamycin" (Registered Trade Mark), chloramphenical and especially penicillin, e.g. procaine penicillin G; (j) hormones, e.g. cortisone.  Examples are (a) streptomycin levo-pimeric-6,8a-cis-endosuccinate; (b) dihydrostreptomycin levo-pimaric-6,8a - cis - endosuccinate; (c) hydroxystreptomycin levo-pimeric-6,8a-cis-endosuccinate; (d) streptomycylidene isonicotinyl hydrazine levo-pimaric - 6,8a - cis - endosuccinate, and the corresponding trans compounds.  Reference has been directed by the Comptroller to Specification 724,863.